RIG-I activation is critical for responsiveness to checkpoint blockade

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Science Immunology  13 Sep 2019:
Vol. 4, Issue 39, eaau8943
DOI: 10.1126/sciimmunol.aau8943

Priming responses to checkpoint blockade

Although activation of intracellular DNA sensing has been proposed as a means to promote antitumor immunity, molecules that regulate sensing of intracellular RNAs have received considerably less attention in this setting. Here, Heidegger et al. report that expression of RNA sensor RIG-I in tumor cells plays a vital role in promoting responsiveness to anti–CTLA-4 therapy in mouse models of cancer. By engineering melanoma cell lines lacking key molecules involved in DNA and RNA sensing, cell death, and type I interferon signaling, the authors have catalogued the relative importance of these pathways in regulating antitumor immunity and responsiveness to checkpoint blockade. The authors propose that activation of RNA sensing could be used to increase the immunogenicity of poorly immunogenic tumors.


Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti–CTLA-4 and its combination with anti–PD-1 rely on tumor cell–intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell–intrinsic RIG-I signaling induced caspase-3–mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103+ dendritic cells, subsequent expansion of tumor antigen–specific CD8+ T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5′– triphosphorylated RNA in both tumor and nonmalignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of DDX58 (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity, and prolonged overall survival. Moreover, in patients with melanoma treated with anti–CTLA-4 checkpoint blockade, high DDX58 RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor–mediated immunotherapy of cancer.

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